title: Specific inhibition of hepatitis C virus entry into host hepatocytes by fungi-derived sulochrin and its derivatives.
abstract: Hepatitis C virus (HCV) is a major causative agent of hepatocellular carcinoma. Although various classes of anti-HCV agents have been under clinical development, most of these agents target RNA replication in the HCV life cycle. To achieve a more effective multidrug treatment, the development of new, less expensive anti-HCV agents that target a different step in the HCV life cycle is needed. We prepared an in-house natural product library consisting of compounds derived from fungal strains isolated from seaweeds, mosses, and other plants. A cell-based functional screening of the library identified sulochrin as a compound that decreased HCV infectivity in a multi-round HCV infection assay. Sulochrin inhibited HCV infection in a dose-dependent manner without any apparent cytotoxicity up to 50 μM. HCV pseudoparticle and trans-complemented particle assays suggested that this compound inhibited the entry step in the HCV life cycle. Sulochrin showed anti-HCV activities to multiple HCV genotypes 1a, 1b, and 2a. Co-treatment of sulochrin with interferon or a protease inhibitor telaprevir synergistically augmented their anti-HCV effects. Derivative analysis revealed anti-HCV compounds with higher potencies (IC50<5 μM). This is the first report showing an antiviral activity of methoxybenzoate derivatives. Thus, sulochrin derivatives are anti-HCV lead compounds with a new mode of action.
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Tokyo University of Science Graduate School of Science and Technology, Noda 278-8510, Japan.
authors.forename: Syo
authors.initials: S
authors.lastname: Nakajima
authors.forename: Koichi
authors.initials: K
authors.lastname: Watashi
authors.forename: Shinji
authors.initials: S
authors.lastname: Kamisuki
authors.forename: Senko
authors.initials: S
authors.lastname: Tsukuda
authors.forename: Kenji
authors.initials: K
authors.lastname: Takemoto
authors.forename: Mami
authors.initials: M
authors.lastname: Matsuda
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Suzuki
authors.forename: Hideki
authors.initials: H
authors.lastname: Aizaki
authors.forename: Fumio
authors.initials: F
authors.lastname: Sugawara
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000494:pharmacology*; D002460:Cell Line; D004357:Drug Synergism; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D022781:Hepatocytes / Q000821:virology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010407:Penicillium / Q000737:chemistry; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D001565:Benzoates; D001688:Biological Products; D016898:Interferon-alpha; D009842:Oligopeptides; C486464:telaprevir; C111298:sulochrin
keywords: Compound; CsA; Entry; HBV envelope protein; HBs; HCV; HCV derived from cell culture; HCV pseudoparticle; HCV trans-complemented particle; HCVcc; HCVpp; HCVtcp; IFN; MOI; Natural product; Screening; Sulochrin; VSV; cyclosporin A; hepatitis C virus; interferon; multiplicity of infection; vesicular stomatitis virus